The type I interferon (IFN) cytokine family comprises the first line of innate defense against virus infections. Mice lacking the IFN receptor (IFNAR1-/-) display high-level virus replication and increased mortality, demonstrating a critical role for IFN in host response to virus infection. However, prevailing models of IFN function assume that these cytokines function solely during acute infection and are dispensable once the adaptive immune response has silenced viral replication. Relatively little is known about potential functions of IFN during chronic or latent infection. We found unexpectedly that IFN prevents reactivation of murine -herpesvirus 68 (MHV68) during latency in vivo. MHV68 is a natural pathogen of mice and displays genetic and pathologic similarities to the human ?-herpesviruses Epstein-Barr virus and Kaposi Sarcoma herpesvirus. The effects of IFN during MHV68 latency did not require the most well characterized IFN-stimulated antiviral genes, which prompted us to consider a novel mechanism. Indeed, our preliminary data show that IFN directly regulates MHV68 latent gene expression via the binding of cellular interferon regulatory factors (IRFs) to viral promoters in latently-infected B cells. This suggests the intriguing hypothesis that -herpesviruses have evolved to integrate their gene expression circuitry with IFN signaling pathways, thereby co-opting a host antiviral system to promote strategic timing of reactivation during periods of immunocompromise. The proposed research uses the tractable MHV68 system to identify the physiologic roles of IFN in regulating viral latent gene expression and reactivation in vivo. Three Specific Aims are proposed to: (i) test the hypothesis that IFN regulates MHV68 infection by acting directly on the infected cell during latency;(ii) identify interferon-regulated viral promoter elements that control replication, gene expression, and reactivation and (iii) define the mechanism by which IRFs regulate latent viral gene expression and reactivation. This research will have broad significance for understanding IFN function during chronic infections and will lead to the identification of host antiviral pathways that may prove relevant for control of oncogenic human??-herpesviruses. PUBLIC HEALTH RELEVANCE: The proposed studies will enhance an understanding of mechanisms by which type I interferons function in chronic infections in humans. Furthermore, as MHV68 is closely related to the human pathogens Epstein-Barr virus and Kaposi sarcoma-associated herpesvirus, these studies will provide new insights into potential therapeutic targets for treatment of cancers arising during latent gammaherpesvirus infection.